Opinion: Synthesizing Life

Designing genomes from scratch will be the next revolution in biology.

By J. Craig Venter | October 1, 2011

J. CRAIG VENTER INSTITUTE

A little over one year ago, my team at the J. Craig Venter Institute announced the construction of the first cell completely controlled by a synthetic genome. After 8 years of work on DNA synthesis, assembly, and error correction, and on new ways to transplant and boot up chromosomes, we succeeded in creating a cell that used only a chemically synthesized chromosome to code for all aspects of the cellular phenotype.

DNA is the software of the cell, and our studies have shown that when we change the software we change the species. Because it is based on the digitized DNA sequence, the design of synthetic genomes provides a true interface between the computer and biological life. While genome design will dominate the future, the field has been limited to a few gene changes as a part of pathway design and to the engineering of novel biological circuits, such as oscillators, that can be used to construct semisynthetic biological machines.

One major limitation is the cost—in both money and time—associated with genome modification. For example, it required over a decade of work and reportedly more than $100 million for the team at DuPont to make a dozen or so modifications to the E. coli genome so that it would convert glucose into propanediol to make “renewably sourced” fibers. And while some clever techniques for codon modification in E. coli have emerged recently from the laboratory of George Church, these are a long way from genomes designed and constructed to perform unique metabolic activities.

The tools and techniques developed by my team to assemble a completely synthetic bacterial genome, while relatively efficient (we built the entire 1.1-million-base-pair synthetic genome in less than one month), are also still quite expensive ($0.30 per base pair) due to the current cost of oligonucleotide synthesis. Fortunately, this work has helped create a demand for rapid, accurate, cheap DNA synthesis, which has led to some very novel approaches that could help reduce these costs. Over the past 23 years, the cost of DNA sequencing has dropped 8 orders of magnitude. Similar improvements with DNA synthesis await technological breakthroughs that are tantalizingly close.

DNA is the software of the cell, and when we change the software we change the species.

Genome design’s greatest limitation is not cost, however, but our fundamental lack of basic biological knowledge. Traditional overemphasis on so-called model organisms has limited scientific discovery largely to mice, which we have learned are not models for humans, and E. coli, which is not a good model for most other bacteria. The gene diversity is far more expansive than most ever imagined. Similar to the limited thinking that labeled noncoding DNA as “junk,” many believed that the new genes discovered during genome sequencing with no matches to known genes were likely to be of little biological significance. But extensive whole-genome shotgun sequencing of environments, ranging from the human gut to the oceans, has taught us that these unknown genes are highly conserved and highly abundant. Our attempts to generate minimal genomes by gene knockouts in the simplest cells show that up to 20 percent of genes essential for life are of unknown function.

These limitations mean that for the immediate future, genome modification and the creation of novel species will be primarily empirically based. We are working on DNA and genome synthesis automation capable of building thousands to millions of genomes per day. Such rapid synthesis will allow for what we call combinatorial genome synthesis—manipulating gene sequences and the order of genes to produce a large variety of genomes. With the use of well-designed screens, new cells with the desired biological properties can be rapidly selected.

Provided we can achieve such rapid synthesis and screening, this approach could become a dramatic new source of biological knowledge. As we overcome the current scientific and technical limitations, I am certain that genome design and construction will become the basis of an industrial and biological revolution that will provide new sources of food, chemicals, fuel, clean water, medicine, vaccines, and other materials. Such tools will offer the opportunity to create self-sustainable systems for long-term space flight, remote military needs, or most importantly, for the future of our planet, where the human population is growing by more than one billion every 12 years. Synthetic biology will clearly be part of the solution we need.

J. Craig Venter is the founder, chairman, and president of The J. Craig Venter Institute, a multidisciplinary genomic-focused research organization formed in October 2006, with locations in Rockville, Maryland, and San Diego, California.

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In this interesting article, Dr. Venter affirms that"DNA is the software of the cell", indicating that the construction andassembly of genomic DNAs would provide us with â€œnovel speciesâ€쳌 in the â€œimmediatefutureâ€쳌. I do not know what immediate future means, but certainly we are farfrom having new species. We may have some synthetic machines able to perform a fewmetabolic activities, which cannot be called â€œspeciesâ€쳌. Today, we know that theregulation of gene activity occurs in several layers with added complexity. Insteadof DNA as the software, I believe these regulatory mechanisms including"epigenetic mechanisms of gene regulation" should be considered asthe software of the cell, working on DNA as the hardware.Â Our knowledge ongene regulation is so primary and little that is hard to believe we would beable to create novel species at least in the â€œimmediate futureâ€쳌.

One must always remember to separate Dr. Venter's (and his team's) astonishing accomplishments from Dr. Venter's overstatement of the claim of "synthesizing life."

It is a truly remarkable and seminal accomplishment to synthesize an entire genome and use it to replace the original genome from a living cell.Â However, I do not believe that I'm the only one that would argue this is not "synthesizing life."Â This is synthesizing one component of the entire living system.Â The next feat would be truly heroic: to synthesize, de novo, all of the component parts and assemble a 100% synthetic cell.

I would also question Dr. Venter's assertion that "...many believed that the new genes discovered during genome sequencing with no matches to known genes were likely to be of little biological significance."Â Who are these many?Â I can't say I recall reading such claims on a widespread basis.Â

In this interesting article, Dr. Venter affirms that"DNA is the software of the cell", indicating that the construction andassembly of genomic DNAs would provide us with â€œnovel speciesâ€쳌 in the â€œimmediatefutureâ€쳌. I do not know what immediate future means, but certainly we are farfrom having new species. We may have some synthetic machines able to perform a fewmetabolic activities, which cannot be called â€œspeciesâ€쳌. Today, we know that theregulation of gene activity occurs in several layers with added complexity. Insteadof DNA as the software, I believe these regulatory mechanisms including"epigenetic mechanisms of gene regulation" should be considered asthe software of the cell, working on DNA as the hardware.Â Our knowledge ongene regulation is so primary and little that is hard to believe we would beable to create novel species at least in the â€œimmediate futureâ€쳌.

One must always remember to separate Dr. Venter's (and his team's) astonishing accomplishments from Dr. Venter's overstatement of the claim of "synthesizing life."

It is a truly remarkable and seminal accomplishment to synthesize an entire genome and use it to replace the original genome from a living cell.Â However, I do not believe that I'm the only one that would argue this is not "synthesizing life."Â This is synthesizing one component of the entire living system.Â The next feat would be truly heroic: to synthesize, de novo, all of the component parts and assemble a 100% synthetic cell.

I would also question Dr. Venter's assertion that "...many believed that the new genes discovered during genome sequencing with no matches to known genes were likely to be of little biological significance."Â Who are these many?Â I can't say I recall reading such claims on a widespread basis.Â

In this interesting article, Dr. Venter affirms that"DNA is the software of the cell", indicating that the construction andassembly of genomic DNAs would provide us with â€œnovel speciesâ€쳌 in the â€œimmediatefutureâ€쳌. I do not know what immediate future means, but certainly we are farfrom having new species. We may have some synthetic machines able to perform a fewmetabolic activities, which cannot be called â€œspeciesâ€쳌. Today, we know that theregulation of gene activity occurs in several layers with added complexity. Insteadof DNA as the software, I believe these regulatory mechanisms including"epigenetic mechanisms of gene regulation" should be considered asthe software of the cell, working on DNA as the hardware.Â Our knowledge ongene regulation is so primary and little that is hard to believe we would beable to create novel species at least in the â€œimmediate futureâ€쳌.

One must always remember to separate Dr. Venter's (and his team's) astonishing accomplishments from Dr. Venter's overstatement of the claim of "synthesizing life."

It is a truly remarkable and seminal accomplishment to synthesize an entire genome and use it to replace the original genome from a living cell.Â However, I do not believe that I'm the only one that would argue this is not "synthesizing life."Â This is synthesizing one component of the entire living system.Â The next feat would be truly heroic: to synthesize, de novo, all of the component parts and assemble a 100% synthetic cell.

I would also question Dr. Venter's assertion that "...many believed that the new genes discovered during genome sequencing with no matches to known genes were likely to be of little biological significance."Â Who are these many?Â I can't say I recall reading such claims on a widespread basis.Â

Sometimes it is editors and publishers who draft headlines, and not those who write articles.Â Headlines of articles and titles of books are known to result in greater sales if they seem to suggest something the author not only would not have said but which causes the author immense discomfort or dissatisfaction.

As to what one has read or heard, progress in learning how nature functions is driven by new findings, sometimes as recently as in the past month, week, day, hour...Â It is not upgraded by going around taking opinion polls on what are the opinions of people at random.Â In fact, progress nowadays can take a considerable amount of time to reach researchers and academicians in other fields, or persons working on unrelated projects in the same field.Â The lag in what reaches writers of textbooks, and thence to be assimilated into current textbooks is such that it would be rare to find a textbook at an advanced level in a field, that contains no obsolescence the day the ink dries on it.

New findings are moving so fast and in so many directions nowadays the even those who spend all their working hours trying to keep up, are hard pressed to do so.

Hopefully this provides some relief to the frustration that is bound to arise for a reader who expects unreasonably that what one hears or reads "on a widespread basis" is incapable of being edited and corrected in a field of science in which new knowledge is erupting not day by day but minute by minute.Â

There has been much debate going on for decades, over what a species "is."

Just as for decades or even centuries there was much debate over what "scientific method" "is."

Nowadays, those who are scientifically literate, are aware that it is not the job of science to pin down a single, lasting lexicographic definition of what something "is," so much as it is the need to adapt one's definition to a continuous stream of new discovery.

Whereas children in primary school were taught a definition of "scientific method" or a definition of "species" that they were led to expect would stand any test thrown against it, the textbooks increasingly teach flexibility and basic understanding of how concepts of how to categorize things must leave leeway for being modified to fit in an evolving process.Â What "works" as a scientific method (or approach) to the gaining of new knowledge in one particular area at the frontiers of new results in science can be quite unlike what "works" at another kind of research.Â

More and more, as with classical physics as compared to quantum physics, new dynamics are seen to "emerge" at the frontiers of different specialties.Â

In a sense, definitions and laws and rules must be left open.Â

In microbiology, some organisms reproduce by dividing and do not multiply by sexual reproduction.Â If one finds, or synthesizes, an engineered cell that reproduces as it is and does, then it meets many kinds of notions of what "species" means.Â If such a definition is useful in the process of research thenit is useful, whether two individuals wish agree or disagree over what word names what it "is."Â

What many a newly discovered or synthesized or theoretically hypothesized thing "is" is what it "is."Â And the important and practical issue revolves around whether those who attempt to test a claimed result, are able to replicate the claimed results of a particular empirical experiment.Â As long as two or more know what they are talking about -- be the particulars about morphology, or or about the ability to breed and reproduce or not, and reproduce... trying to stamp such things with the necessity of conforming to a strict inflexible list of subsumptive relations would be equivalent to saying, "It is not good science to find or fabricate something that is new and different."

That's what science does best:Â find things that are anomalous, whether in some one small way or in many profound ways.Â Its highest and best purpose is not to conform to entrenched conservative categorizations, and require a new word for every nuance.Â The general field of bio-science already has so many words that learning very much about it has become comparable to learning a new language.

At the frontiers of some fields there is so much potential, and so voluminous new data being evaluated, that some flexibility -- some elbow room in conversing about all this stuff is not only useful but unavoidable.

The casual reader of popular science cannot help but find this frustrating.Â However, let us allow that if two individuals working on the same issue in some specialized frontier know they are talking about the same thing when they use a certain term in a certain context, each knows what the other is talking about.

Sometimes it is editors and publishers who draft headlines, and not those who write articles.Â Headlines of articles and titles of books are known to result in greater sales if they seem to suggest something the author not only would not have said but which causes the author immense discomfort or dissatisfaction.

As to what one has read or heard, progress in learning how nature functions is driven by new findings, sometimes as recently as in the past month, week, day, hour...Â It is not upgraded by going around taking opinion polls on what are the opinions of people at random.Â In fact, progress nowadays can take a considerable amount of time to reach researchers and academicians in other fields, or persons working on unrelated projects in the same field.Â The lag in what reaches writers of textbooks, and thence to be assimilated into current textbooks is such that it would be rare to find a textbook at an advanced level in a field, that contains no obsolescence the day the ink dries on it.

New findings are moving so fast and in so many directions nowadays the even those who spend all their working hours trying to keep up, are hard pressed to do so.

Hopefully this provides some relief to the frustration that is bound to arise for a reader who expects unreasonably that what one hears or reads "on a widespread basis" is incapable of being edited and corrected in a field of science in which new knowledge is erupting not day by day but minute by minute.Â

There has been much debate going on for decades, over what a species "is."

Just as for decades or even centuries there was much debate over what "scientific method" "is."

Nowadays, those who are scientifically literate, are aware that it is not the job of science to pin down a single, lasting lexicographic definition of what something "is," so much as it is the need to adapt one's definition to a continuous stream of new discovery.

Whereas children in primary school were taught a definition of "scientific method" or a definition of "species" that they were led to expect would stand any test thrown against it, the textbooks increasingly teach flexibility and basic understanding of how concepts of how to categorize things must leave leeway for being modified to fit in an evolving process.Â What "works" as a scientific method (or approach) to the gaining of new knowledge in one particular area at the frontiers of new results in science can be quite unlike what "works" at another kind of research.Â

More and more, as with classical physics as compared to quantum physics, new dynamics are seen to "emerge" at the frontiers of different specialties.Â

In a sense, definitions and laws and rules must be left open.Â

In microbiology, some organisms reproduce by dividing and do not multiply by sexual reproduction.Â If one finds, or synthesizes, an engineered cell that reproduces as it is and does, then it meets many kinds of notions of what "species" means.Â If such a definition is useful in the process of research thenit is useful, whether two individuals wish agree or disagree over what word names what it "is."Â

What many a newly discovered or synthesized or theoretically hypothesized thing "is" is what it "is."Â And the important and practical issue revolves around whether those who attempt to test a claimed result, are able to replicate the claimed results of a particular empirical experiment.Â As long as two or more know what they are talking about -- be the particulars about morphology, or or about the ability to breed and reproduce or not, and reproduce... trying to stamp such things with the necessity of conforming to a strict inflexible list of subsumptive relations would be equivalent to saying, "It is not good science to find or fabricate something that is new and different."

That's what science does best:Â find things that are anomalous, whether in some one small way or in many profound ways.Â Its highest and best purpose is not to conform to entrenched conservative categorizations, and require a new word for every nuance.Â The general field of bio-science already has so many words that learning very much about it has become comparable to learning a new language.

At the frontiers of some fields there is so much potential, and so voluminous new data being evaluated, that some flexibility -- some elbow room in conversing about all this stuff is not only useful but unavoidable.

The casual reader of popular science cannot help but find this frustrating.Â However, let us allow that if two individuals working on the same issue in some specialized frontier know they are talking about the same thing when they use a certain term in a certain context, each knows what the other is talking about.

Sometimes it is editors and publishers who draft headlines, and not those who write articles.Â Headlines of articles and titles of books are known to result in greater sales if they seem to suggest something the author not only would not have said but which causes the author immense discomfort or dissatisfaction.

As to what one has read or heard, progress in learning how nature functions is driven by new findings, sometimes as recently as in the past month, week, day, hour...Â It is not upgraded by going around taking opinion polls on what are the opinions of people at random.Â In fact, progress nowadays can take a considerable amount of time to reach researchers and academicians in other fields, or persons working on unrelated projects in the same field.Â The lag in what reaches writers of textbooks, and thence to be assimilated into current textbooks is such that it would be rare to find a textbook at an advanced level in a field, that contains no obsolescence the day the ink dries on it.

New findings are moving so fast and in so many directions nowadays the even those who spend all their working hours trying to keep up, are hard pressed to do so.

Hopefully this provides some relief to the frustration that is bound to arise for a reader who expects unreasonably that what one hears or reads "on a widespread basis" is incapable of being edited and corrected in a field of science in which new knowledge is erupting not day by day but minute by minute.Â

There has been much debate going on for decades, over what a species "is."

Just as for decades or even centuries there was much debate over what "scientific method" "is."

Nowadays, those who are scientifically literate, are aware that it is not the job of science to pin down a single, lasting lexicographic definition of what something "is," so much as it is the need to adapt one's definition to a continuous stream of new discovery.

Whereas children in primary school were taught a definition of "scientific method" or a definition of "species" that they were led to expect would stand any test thrown against it, the textbooks increasingly teach flexibility and basic understanding of how concepts of how to categorize things must leave leeway for being modified to fit in an evolving process.Â What "works" as a scientific method (or approach) to the gaining of new knowledge in one particular area at the frontiers of new results in science can be quite unlike what "works" at another kind of research.Â

More and more, as with classical physics as compared to quantum physics, new dynamics are seen to "emerge" at the frontiers of different specialties.Â

In a sense, definitions and laws and rules must be left open.Â

In microbiology, some organisms reproduce by dividing and do not multiply by sexual reproduction.Â If one finds, or synthesizes, an engineered cell that reproduces as it is and does, then it meets many kinds of notions of what "species" means.Â If such a definition is useful in the process of research thenit is useful, whether two individuals wish agree or disagree over what word names what it "is."Â

What many a newly discovered or synthesized or theoretically hypothesized thing "is" is what it "is."Â And the important and practical issue revolves around whether those who attempt to test a claimed result, are able to replicate the claimed results of a particular empirical experiment.Â As long as two or more know what they are talking about -- be the particulars about morphology, or or about the ability to breed and reproduce or not, and reproduce... trying to stamp such things with the necessity of conforming to a strict inflexible list of subsumptive relations would be equivalent to saying, "It is not good science to find or fabricate something that is new and different."

That's what science does best:Â find things that are anomalous, whether in some one small way or in many profound ways.Â Its highest and best purpose is not to conform to entrenched conservative categorizations, and require a new word for every nuance.Â The general field of bio-science already has so many words that learning very much about it has become comparable to learning a new language.

At the frontiers of some fields there is so much potential, and so voluminous new data being evaluated, that some flexibility -- some elbow room in conversing about all this stuff is not only useful but unavoidable.

The casual reader of popular science cannot help but find this frustrating.Â However, let us allow that if two individuals working on the same issue in some specialized frontier know they are talking about the same thing when they use a certain term in a certain context, each knows what the other is talking about.